The liver is a major determinant of xenobiotic metabolism. Much is known about factors which influence the hepatic metabolism and excretion of foreign compounds. Alterations in the metabolic or excretory function of the liver often bear dramatically on the intensity and/or duration of xenobiotic action. It is known that other organs, such as the small intestine (SI) are capable of performing many of the same metabolic conversions as the liver, but it is not yet clear whether extrahepatic metabolism contributes significantly to the overall in vivo disposition of foreign compounds. An attempt will be made to elucidate the importance of intestinal glucuronide formation to the hepatic disposition of a model compound, diethylstilbestrol (DES). Appearance of DES and its monoglucuronide (DESG) in the efferent mesenteric venous blood of isolated rat gut loops with intact arterial supply will be used to monitor intestinal absorption and metabolism of DES under a variety of conditions. These will include varying dosage, use of different areas of the intestine, and pretreatment with cortisone and lincomycin. The isolated perfused rat liver will be used to determine whether alterations in the ratio of DES or DESG could be expected to yield differences in the hepatic disposition of DES-related material. Finally, plasma levels and biliary excretion of DES-related material will be measured in animals intact except for a biliary fistula to learn whether manipulations which alter intestinal DES metabolism but which do not directly affect hepatic DES disposition are capable of altering the overall disposition of DES in the rat. Later studies will focus on changes in intestinal DES absortion and conjugation under several conditions, including the presence and absence of chyme, fasting, starvation, previous exposure to DES and stimulators of hepatic mixed function oxidase, and pregnancy. The applicability of results gained with DES to other compounds will be tested with morphine, naphthol and chloramphenicol. BIBLIOGRAPHIC REFERENCE: J. Lasker and D.E. Rickert. Absorption and glucuronidation of diethylstilbestrol by the rat small intestine. Fed. Proc., in press, 1977.